The present invention relates to small molecule inhibitors of ERG oncoprotein and the use of such compounds as candidate therapeutics for treating ERG positive cancers, including prostate cancer (CaP). CaP is the most frequently diagnosed non-skin malignancy and second leading cause of cancer related deaths among men in the western countries. While early detected CaP due to PSA screening is managed effectively by surgery or radiation, a significant subset of CaP patients (20% to 40%) experience disease recurrence after definitive treatment and will require hormone ablation therapy. Despite initial response to therapy, metastatic CaP tumors eventually become refractory to hormone ablation therapy. For this subset of patients, namely, those having metastatic hormone refractory cancer there is no effective cure.
The ERG proto-oncogene belongs to a large family of ETS transcription factors that are both positive and negative regulators of gene expression (Watson et al., 2010). These transcription factors are downstream effectors of the mitogenic signal transduction pathways involved in cell proliferation, cell differentiation, development, transformation, apoptosis, and immune regulation (Watson et al., 2010; Sreenath et al., 2011). The ERG gene is the most prevalent and validated genomic alteration in prostate cancer. Recurrent TMPRSS2-ERG gene fusions are present in nearly half of all CaP patients in western countries. This gene fusion results in male hormone dependent and tumor cell specific expression of a truncated ERG protein (deletion of 32 amino terminal residues). ERG alterations and the overexpression of ERG protein, therefore, are implicated in the development and progression of CaP.
ERG expression in CaP is AR dependent. While there are a number of androgen receptor (AR) signaling inhibitors already being used as therapeutics for treating CaP, the present inventors were not previously aware of compounds that can selectively inhibit ERG expression. Accordingly, the invention describes small organic molecules that selectively inhibit ERG expression.